Common Variable Immunodeficiency Disorders in Children: Delayed Diagnosis Despite Typical Clinical Presentation SIMON URSCHEL, MD, LALE KAYIKCI, MD, UWE WINTERGERST, MD, GUNDULA NOTHEIS, MD, ANNETTE JANSSON, MD, AND BERND H. BELOHRADSKY, MD Objective To characterize common variable immunodeficiency disorder (CVID) in childhood. Study design We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. Results Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). Conclusions CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders. (J Pediatr 2009;154:888-94) C ommon variable immunodeficiency disorders (CVID) represent the most frequent symptomatic primary immunode- ficiency in North America and Europe, 1 with an incidence of 1:25 000 to 1:66 000. 2 The diagnosis requires a history of recurrent or chronic bacterial infections, significant reduction of immunoglobulin G (IgG) (2 standard deviations), reduction of immunoglobulin A (IgA) or immunoglobulin M (IgM), as well as a defective specific antibody production after vaccination 3 (www.ESID.org). Secondary reasons for hypogammaglobulinemia, such as chromosomal aberrations, medical treatment, leukemia, renal, or gastrointestinal loss of immunoglobulins must be excluded. 4 This definition is focused on clinical findings and the lack of specific humoral immune responses. The latter is the result of a complex interaction of antigen-presenting cells, T- and B-lymphocytes. Thus a variety of different defects within this system may lead to the findings defining CVID. Linkage analyses suggest a genetic background for CVID supported by familial coincidence of CVID or related immunoglobulin deficien- cies, which occur in a minority of patients. 1 However, only a few mutations have yet been found to be causative for CVID. Defects of the inducible costimulator 5 are present in a small percentage of patients. 6 Mutations in the CD19 gene were found in single patients, and defects in the interaction of TACI and BAFF-receptor have been shown to influence the risk for development of CVID. 7,8 The typical delayed onset after a period of normal health status supports the hypothesis that CVID is often the result of genetic predispo- sition and critical events, such as infections or toxic events. There have been recent attempts to define distinct clinical or immunologic subgroups. 9,10 The age at diagnosis shows 2 peaks, between 6 and 10 years of age and in young adulthood (between 26 and 40 years). 11 Recently published registry data do not as clearly reflect this age distribution. 9 Although adult onset of the disease has been well described CVID Common variable immunodeficiency disorders FACS Flow cytometry (Fluorescent-activated cell sorting) IgA Immunoglobulin A IgG Immunoglobulin G IgM Immunoglobulin M IVIG Intravenous immunoglobulin From the Pediatric Immunology and Infec- tious Diseases, University Children’s Hospi- tal, Ludwig Maximilians University (S.U., L.K., U.W., G.N., A.J., B.B.), and the Pediatric Cardiology and Intensive Care, University College Hospital Grosshadern (S.U.), Mu- nich, Germany. There are no funding or financial affiliations influencing the content of the manuscript or leading to a conflict of interest. Submitted for publication Apr 29, 2008; last revision received Oct 8, 2008; accepted Dec 5, 2008. Reprint requests: Dr. Simon Urschel, Pedi- atric Immunology and Infectious Diseases, Dr. von Haunersches Kinderspital, Ludwig Maximilians University, Lindwurmstr. 4, 80337 Munich, Germany. E-mail: simon. [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.12.020 888
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